Bissonnette E Y, Enciso J A, Befus A D
Department of Medicine, University of Alberta, Edmonton, Canada.
J Immunol. 1996 Jan 1;156(1):218-23.
Sulfasalazine is an effective treatment in some inflammatory diseases that exhibit mast cell (MC) hyperplasia. However, its effect on MC has been incompletely studied. We have established that sulfasalazine inhibits the release of histamine and TNF-alpha from MC. Sulfasalazine and its metabolites, 5-aminosalicylic acid (5-ASA) and to a lesser extent sulfapyridine, inhibited Ag-stimulated histamine release from rat peritoneal MC in a concentration-dependent manner with a 50% inhibitory concentration of 6 x 10(6)M, 8 x 10(-6)M, and 3 x 10(-4)M, respectively. Similar results were observed with sulfapyridine and 5-ASA on Ag-stimulated histamine release of another population of MC, namely rat intestinal mucosal MC, but sulfasalazine was markedly less potent than its metabolites. Interestingly, sulfasalazine and sulfapyridine, but not 5-ASA, inhibited Ag-stimulated TNF-alpha released by MC. Similar results were observed with MC-mediated cytotoxic activity in which sulfasalazine and sulfapyridine, but nor 5-ASA, inhibited MC TNF-alpha-dependent cytotoxicity in a concentration-dependent manner. The addition of sulfasalazine to MC, up to 12 h after the cytotoxic assay (16 h) had started, significantly inhibited cytotoxic activity, suggesting that sulfasalazine inhibited the cytotoxic mediator, TNF-alpha. Indeed, affinity studies demonstrated that sulfasalazine binds TNF-alpha. Furthermore, the inhibition of MC cytotoxicity by sulfasalazine appeared to require new protein synthesis. Pretreatment of MC with sulfasalazine also inhibited the release of TNF-alpha and reduced the levels of TNF-alpha mRNA. Thus, sulfasalazine inhibits MC-mediated, TNF-alpha-dependent cytotoxicity by multiple mechanisms: competitive inhibition of soluble TNF-alpha, reduction of levels of TNF-alpha mRNA, and inhibition of TNF-alpha release.
柳氮磺胺吡啶是治疗某些表现为肥大细胞（MC）增生的炎症性疾病的有效药物。然而，其对MC的作用尚未得到充分研究。我们已经证实柳氮磺胺吡啶可抑制MC释放组胺和肿瘤坏死因子-α（TNF-α）。柳氮磺胺吡啶及其代谢产物5-氨基水杨酸（5-ASA）以及程度较轻的磺胺吡啶，以浓度依赖的方式抑制抗原刺激的大鼠腹膜MC释放组胺，其50%抑制浓度分别为6×10⁻⁶M、8×10⁻⁶M和3×10⁻⁴M。磺胺吡啶和5-ASA对另一群MC即大鼠肠黏膜MC的抗原刺激组胺释放也观察到类似结果，但柳氮磺胺吡啶的效力明显低于其代谢产物。有趣的是，柳氮磺胺吡啶和磺胺吡啶可抑制MC释放抗原刺激的TNF-α，但5-ASA无此作用。在MC介导的细胞毒性活性方面也观察到类似结果，其中柳氮磺胺吡啶和磺胺吡啶可浓度依赖性地抑制MC TNF-α依赖性细胞毒性，但5-ASA无此作用。在细胞毒性试验（16小时）开始后长达12小时向MC中添加柳氮磺胺吡啶，可显著抑制细胞毒性活性，提示柳氮磺胺吡啶抑制细胞毒性介质TNF-α。实际上，亲和力研究表明柳氮磺胺吡啶可结合TNF-α。此外，柳氮磺胺吡啶对MC细胞毒性的抑制似乎需要新的蛋白质合成。用柳氮磺胺吡啶预处理MC也可抑制TNF-α的释放并降低TNF-α mRNA水平。因此，柳氮磺胺吡啶通过多种机制抑制MC介导的、TNF-α依赖性细胞毒性：对可溶性TNF-α的竞争性抑制、降低TNF-α mRNA水平以及抑制TNF-α释放。
